Diabetic nephropathy is a leading cause of morbidity and mortality in diabetic patients. With the rising epidemic of diabetes in both developing and developed countries, diabetes is now the leading cause of end stage renal disease (ESRD), accounting for 40-50% of all new patients on renal replacement therapy (Ritz E, Rychlik I, Locatelli F, Halimi S, End-stage renal failure in type 2 diabetes: a medical catastrophe of worldwide dimensions, Am J Kidney Dis, 1999; 34:795-808). China is one of the 3 top countries with the most number of diabetic people estimated to increase to 40 million in 2025 with the predominant increase occurring in the middle aged population (Chan J. C. N, Ng M. C. Y, Critchley J. A. J. H, Lee S. C, Cockram C. S, Diabetes mellitus—a special medical challenge from a Chinese perspective, Diabetes Research and Clinical Practice, 2001; 54:S19-27). This is mainly due to the rising prevalence of young onset diabetes and childhood obesity and metabolic syndrome (Chan J. C. N, Ng M. C. Y, Lessons learned from young onset diabetes in China, Current Diabetes Report, 2003; 3:101-107; Chan J. C. N, Cheung C. K, Cheung M. Y. F, Swaminathan R, Critchley J. A. J. H, Cockram C. S, Abnormal albuminuria as a predictor of mortality and renal impairment in Chinese patients with NIDDM, Diabetes Care, 1995; 18:1013-1014; Chan J. C. N, Ko G. T. C, Leung D, Cheung R. C. K, Cheung M, So W. Y, et al, The long term effects of angiotensin converting enzyme inhibition and metabolic control on cardiovascular and renal outcomes in hypertensive Type 2 diabetic patients, Kidney International, 2000; 57:590-600). In the World Health Organization Multinational Study for Vascular Diseases in Diabetes (WHO-MSVDD), Asian, notably Chinese and Japanese patients, had higher incidence of ESRD than Caucasian type 2 diabetic patients (Morrish N. J, Wang S, Stevens L. K, Fuller J. H, Keen H, Mortality and causes of death in the WHO Multinational Survey of Vascular Diseases in Diabetes, Diabetologia, 2001; 44:S14-21).
In contrast to the Caucasian diabetic population in whom the majority of patients die from cardiovascular events, ESRD is an important cause of death in Chinese diabetic patients (Chan J. C. N, Cheung C. K, Cheung M Y F, Swaminathan R, Critchley J. A. J. H, Cockram C. S, Abnormal albuminuria as a predictor of mortality and renal impairment in Chinese patients with NIDDM, Diabetes Care, 1995; 18:1013-1014). These findings have recently been confirmed by the WHO-MSVDD (Morrish N. J, Wang S, Stevens L. K, Fuller J. H, Keen H, Mortality and causes of death in the WHO Multinational Survey of Vascular Diseases in Diabetes, Diabetologia, 2001; 44:S14-21). In keeping with these findings, it is now recognized there are inter-ethnic differences in the allele frequency or haplotypes of disease-associated genes which may contribute to the racial differences in susceptibility to disease development (Ng M, Wang Y, So W, Cheng S, Visvikis S, Zee R, et al, Ethnic differences in the linkage disequilibrium and distribution of single nucleotide polymorphisms in 35 candidate genes for cardiovascular diseases, Genomics, 2003: in press; Young R P, Thomas G N, Critchley J. A. J. H, Tomlinson B, Woo K. S, Sanderson J. E, Interethnic differences in coronary heart disease mortality in 25 populations: associations with the angiotensin converting enzyme DD genotype frequency, Journal of Cardiovascular Risk, 1998; 5:303-7). Given the effect of duration of disease on development of complications, rising prevalence of young and middle aged diabetic population and the racial predilection to develop diabetic renal disease, there is a looming epidemic of renal failure and cardiovascular diseases in our increasingly young population with its socioeconomic implications (Chan J. C. N, Ng M. C. Y, Critchley J. A. J. H, Lee S. C, Cockram C. S, Diabetes mellitus—a special medical challenge from a Chinese perspective, Diabetes Research and Clinical Practice, 2001; 54:S19-27).
We have previously reported the high prevalence of nephropathy ranging from 30% to 50% and the predictive value of this urinary marker for mortality and deterioration of renal function in Chinese diabetic subjects (Chan J C N, Cheung C K, Cheung M Y F, Swaminathan R, Critchley J A J H, Cockram C S, Abnormal albuminuria as a predictor of mortality and renal impairment in Chinese patients with NIDDM, Diabetes Care, 1995; 18:1013-1014; So W Y, Chan N, Tong P C Y, Chow C C, Chan W B, Ng M C Y, Chan J C N, Effect of RAAS inhibition on survival and renal outcomes in 3737 Chinese Type 2 diabetic patients, Hypertension. 2004; 44: 294-9).
Apart from hypertension and dyslipidemia, we have reported the independent association between insulin resistance and diabetic nephropathy (Chan J. C. N, Tomlinson B, Nicholls M. Q Swaminathan R, Cheung C. K, Cockram C S, Albuminuria, insulin resistance and dyslipidaemia in Chinese patients with non-insulin-dependent diabetes (NIDDM), Diabetic Medicine, 1996; 13:150-55) as well as the intimate relationships between obesity, albuminuria and dysglycemia in Chinese subjects (Lee Z, Critchley J, Ko G T, Anderson P, Thomas N, Young R, et al, Obesity and cardiovascular risk factors in Hong Kong Chinese, Obesity Reviews, 2002; 3:178-182). Family-based studies and segregation analysis (The Diabetes Control and Complications Trial Research Group, Clustering of long term complications in families with diabetes in the diabetes control and complication trial, Diabetes, 1997; 46:1829-1839) as well as genome scan (Imperatore G Hanson R L, Pettitt D, Kobes S, Bennett P, Knowler W, Sib pair linkage analysis for susceptibility genes for microvascular complications among Pima Indians with type 2 diabetes. Pima Diabetes Gene Group, Diabetes, 1998; 47:821-30; Imperatore Q Knowler W, Pettitt D, Kobes S, Bennett P, Hanson R, Segregation analysis of diabetic nephropathy in Pima Indians, Diabetes, 2000; 49:1049-56) have confirmed strong genetic components in the development of diabetic renal disease. The renin angiotensin system (RAS) plays a pivotal role in the regulation of systemic and renal haemodynamics as well as cellular and tissue growth (Cooper M, Pathogenesis, prevention and treatment of diabetic nephropathy, Lancet, 1998; 352:213-9). The TT genotype of the AGT M235T polymorphism and the D allele of the ACE I/D polymorphism have been associated with diabetic nephropathy in Caucasian, Japanese and Chinese diabetic patients (Fujisawa T, Ikegami H, Kawaguchi Y, Hamada Y, Ueda H, Shintani M, et al, Meta analysis of association of insertion/deletion polymorphism of angiotensin I converting enzyme gene with diabetic nephropathy and retinopathy, Diabetologia, 1998; 41:47-53; Young R. P, Chan J. C. N, Poon E, Critchley J. A. J. H, Cockram C. S, Associations between albuminuria and angiotensinogen T235 and angiotensin converting enzyme insertion/deletion polymorphisms in Chinese NIDDM patients, Diabetes Care, 1997; 21:431-7; Ringel J, Beige J, Kunz R, Distler A, Sharma A, Genetic variants of the renin angiotensin system, diabetic nephropathy and hypertension, Diabetologia, 1997; 40:193-9, Wang Y, Ng M, So W, Tong P, Ma R, Chow C, Cockram C, J C N Chan. Prognostic effect of insertion/deletion polymorphism of the ace gene on renal and cardiovascular clinical outcomes in Chinese patients with type 2 diabetes. Diabetes Care, 2004; 28: 348-54).
Tumor necrosis factor alpha (TNF-α), a cytokine secreted by adipocytes, is the linking factor for obesity-related insulin resistance (Hotamisligil G S, Spiegelman B M, Tumor necrosis factor: a key component of the obesity-diabetes link, Diabetes, 1994; 43:1271-8), the latter being an important feature of diabetic nephropathy, including Chinese patients (Chan J. C. N, Tomlinson B, Nicholls M. G S Swaminathan R, Cheung C. K, Cockram C. S, Albuminuria, insulin resistance and dyslipidaemia in Chinese patients with non-insulin-dependent diabetes (NIDDM), Diabetic Medicine, 1996; 13:150-55). A recent Japanese study has shown a positive association between elevated serum TNF-α level and nephropathy in Type 2 diabetic patients (Moriwaki Y, Yamamoto T, Shibutani Y, Aoki E, Tsutsumi Z, Takahashi S, et al, Elevated levels of interleukin 18 and tumor necrosis factor alpha in serum of patients with type 2 diabetes mellitus: relationship with diabetic nephropathy, Metabolism: Clinical and Experimental, 2003; 52:605-8). In this regard, the G-308A polymorphism in the promoter region of TNF-α gene had been reported to be associated with obesity and insulin resistance (Dalziel B, Goskby A, Richman R, Bryson J, Caterson I, Association of TNF alpha -308 G/A promoter polymorphism with insulin resistance in obesity, Obesity Research, 2002; 10:401-7) and increased transcriptional activity of TNF-α (Kroeger K, Carville K, Abraham L, The -308 tumor necrosis factor alpha promoter polymorphism effects transcription, Molecular Immunology, 1997; 34:391-99). Aldose reductase (ALR2) is the key enzyme in the polyol pathway which can lead to increased oxidative stress and alteration of intracellular milieu causing diabetic microangiopathy (Hodgkinson A, Sondergaard K, Yang B, Cross D, Millward B, Demaine A, Aldose reductase expression is induced by hyperglycemia in diabetic nephropathy, Kidney International, 2001; 60:211-8). Both the z−2 allele of 5′-(CA) and T allele of C-106T polymorphisms of this gene have been shown to increase risk for nephropathy in Type 1 and Type 2 diabetic patients including Chinese (Wang Y, Ng M, Lee S, So W, Tong C, Cockram C, et al, Phenotypic heterogeneity associations of two aldose reductase gene polymorphisms with nephropathy and retinopathy in Type 2 diabetes, Diabetes Care, 2003; 26:2410-5). These putative genetic factors further interact with metabolic, hemodynamic and growth factors to cause proteinuria and progressive decline in renal function (Parving H. H, Tarnow L, Rossing P, Genetics of diabetic nephropathy, Journal of American Society of Nephrology, 1996; 7:2509-17).
Although there have been reports on the associations between these 5 genetic markers and diabetic complications in Caucasian and Japanese populations, there have been scanty and inconsistent reports in Chinese diabetic populations. To date, there have been no reports showing the interactive effects of these genetic factors on development of diabetic complications including diabetic nephropathy.
One of the promises of applied genomics lies in its potential use to identify at risk subjects for early and targeted intervention to preserve health and reduce the impact of killing diseases such as diabetes (Collins F, Green E, Guttmacher A, Guyer MobotuNHGRI, A vision for the future of genomics research. A blueprint for the genomic era, Nature, 2003; 422:835-47). In our search for genetic factors to identify high risk subjects for complications in Chinese diabetic patients, we were the first group to report the association between the AGT TT genotype and diabetic nephropathy and its synergistic effects with ACE D allele on its development (Young R P, Chan J. C. N, Poon E, Critchley J. A. J. H, Cockram C. S, Associations between albuminuria and angiotensinogen T235 and angiotensin converting enzyme insertion/deletion polymorphisms in Chinese NIDDM patients, Diabetes Care, 1997; 21:431-7) as well as the independent predictive role of ACE DD genotype on development of ESRD (Wang Y, Ng M, So W, Tong P, Ma R, Chow C, Cockram C, JCN Chan. Prognostic effect of insertion/deletion polymorphism of the ace gene on renal and cardiovascular clinical outcomes in Chinese patients with type 2 diabetes. Diabetes Care 2004; 28:348-54). Similarly, we were also the first group to report the risk association between ALR2 TT genotype (Wang Y, Ng M, Lee S, So W, Tong C, Cockram C, et al, Phenotypic heterogeneity associations of two aldose reductase gene polymorphisms with nephropathy and retinopathy in Type 2 diabetes, Diabetes Care, 2003; 26:2410-5) and diabetic nephropathy in subjects of Chinese descent.